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  1. 1. November 2001 Endocrinology Volume 1, Issue 1 AS PRESENTED IN THE ROUNDS R OUNDS ™ OF THE DIVISION ST. MICHAEL’S OF ENDOCRINOLOGY AND METABOLISM, HOSPITAL Combination therapy with oral hypoglycemic agents: Leading with Innovation Serving with Compassion Rationale and principles ST. MICHAEL’S HOSPITAL A teaching hospital affiliated with the University of Toronto A M I R K . H A N N A , M B, B C H , F R C P C , F A C P UNIVERSITY OF TORONTO The objective of this inaugural issue of Endocrinology Rounds is to review the impact of intensive and early glucose control on the complications of diabetes, understand the characteristics of the different classes of oral hypoglycemic agents, highlight the benefits Members of the Division of of combination therapy with oral hypoglycemic agents, and provide an overview of recent Endocrinology and Metabolism combination therapy studies. at St. Michael’s Hospital L. LEITER, MD (HEAD) Studies in people with type 1 and 2 diabetes1-3 have demonstrated that intensive treat- EDITOR, ENDOCRINOLOGY ROUNDS ment of hyperglycemia results in significant reduction in microvascular complications and a tendency for decreased macrovascular disease. Epidemiological analyses of the United G. BOOTH, MD Kingdom Prospective Diabetes Study (UKPDS)4 found a continuous relationship between P. CONNELLY, PHD glucose levels and both micro- and macrovascular disease. The DCCT/EDIC (Diabetes Control and Complications Trial/Epidemiology of Dia- C. DERZKO, MD betes Interventions and Complications Research Group) study 5 followed up most of the J. GOGUEN, MD original cohort of the DCCT for 4 years after the original results were analyzed. The group A. HANNA, MD initially assigned to intensive treatment continued to show significantly less microvascular complications when compared to the conventional treatment group, even though the D. JENKINS, MD, PHD difference in HbA1c values between the 2 groups became much smaller. In the Kumamoto R. JOSSE, MB 8-year update study, differences in HbA1c between the intensive and conventional groups, T. MURRAY, MD seen at the end of the first 6 years of the study, were maintained. Continuing protection from microvascular complications was noted.6 D. NG, MD Management protocols derived from The Clinical Practice Guidelines for the Manage- R. PATTEN, MD ment of Diabetes in Canada7 recommend a step-wise approach to glucose control in people L. RAO, PHD with type 2 diabetes. This approach commences with life-style changes and is followed by oral agent monotherapy, combinations of oral agents, and finally, adding or substituting W. SINGER, MD insulin. Moving from one step of treatment to the next is recommended when target levels R. VOLPE, MD of blood glucose are not attained after a waiting period of 2 to 4 months. This approach, V. VUKSAN, PHD however, accepts treatment failure and tolerates the detrimental effects of glucose toxicity on insulin secretion and sensitivity. T. WOLEVER, MD, PHD A new paradigm of early utilization of combination therapy has, therefore, been sug- M. WOO, M.D, PHD gested. It is aimed at attaining ideal blood glucose levels early on in the course of therapy. This approach is followed by efforts to maintain these ideal levels with frequent measure- ments of pre- and postprandial glucose levels, HbA1c. Target levels of these variables are based on those found in people without diabetes (eg, a HbA1c level that is < 6%). This St. Michael’s Hospital approach has the following benefits: 6121-61 Queen St. E. • it targets the different pathogenetic factors contributing to hyperglycemia, (ie, insulin Toronto, Ont. M5C 2T2 Fax: (416) 867-3696 resistance, impaired beta cell function, and increased hepatic glucose production); • it uses sub-maximal doses of different oral agents, decreasing the possible side effects of The editorial content of Endocrinology such medications; Rounds is determined solely by the Division of Endocrinology and Metabolism, • it avoids the effects of glucose toxicity. St. Michael’s Hospital, University of Toronto.
  2. 2. There are two studies – Action to Control Cardio- Insulin sensitizers vascular Disease in Diabetes (ACCORD) and the VA The thiazolidinediones: pioglitazone and rosiglitazone Diabetes Trial 8,9 – that are now evaluating the effect of attaining normal glycemia (HbA1c < 6%), among other Pioglitazone and rosiglitazone are members of the interventions, on the occurrence of macrovascular com- thiazolidinedione family, a group of insulin sensitizing plications in patients with type 2 diabetes. agents that enhance sensitivity to insulin in adipose tissue, striated muscle and, to a lesser extent, in the liver. Characteristics of the different classes of They decrease hepatic glucose production and increase oral hypoglycemic agents insulin-mediated glucose uptake. The mechanism of Insulin secretagogues action is not fully elucidated. Both agents are known to Insulin secretagogues act by binding to the different bind to the nuclear receptor PPAR–γ (peroxisome prolif- sulfonylurea receptor sites on the plasma membrane of erator-activated receptor–gamma), which regulates the beta cells in the pancreatic islets. The resulting closure of transcription of several genes involved in insulin-medi- the KATP channels leads to membrane depolarization, ated glucose uptake in peripheral tissues, bringing about opening of the calcium channels, and influx of calcium, increased glucose transporter translocation (GLUT- 4) to resulting in insulin secretion. This group of drugs is the cell membrane. Their effect appears to be achieved utilized in an attempt to correct the quantitative (overall primarily by direct action on fat cells. Both drugs, decreased insulin secretion in response to hyperglycemia) therefore, amplify insulin action and reduce insulin and qualitative (absent first phase insulin secretion) resistance.18-20 abnormalities of insulin secretion in type 2 diabetes. The glucose-lowering effect of these drugs is similar Sulfonylureas increase insulin secretion; however, to the sulphonylureas. In patients naïve to oral agents, only some members of this class partially restore first the decrease in HbA1c ranges between 0.8% and 1.9%, phase insulin excursion. This group of drugs is usually depending on the dose used. In a group of patients with well tolerated, effective in lowering blood glucose, type 2 diabetes previously treated with other oral hypo- but has a 1%-10% yearly secondary failure rate. Hypo- glycemic agents, the decrease in HbA1c ranged between glycemia and weight gain are the main side effects, the 0.3 and 0.9%.21-25 Thiazolidinediones are slow to reach magnitude of which vary among different members of their maximum therapeutic effect, taking between 8-12 this class. Gliclazide and glimepiride tend to be associated weeks to do so. In a study that compared rosiglitazone with less hypoglycemia and weight gain.10,11 with pioglitazone in patients with type 2 diabetes previ- ously treated with troglitazone, there was no difference in Meglitinide analogues glycemic control as measured by HbA1c.24 Other charac- These drugs represent a new family of insulin secreta- teristics of these drugs are shown in Table 1. gogues. Structurally, they are non-sulfonylurea agents. They are absorbed rapidly, stimulate insulin release Side effects of pioglitazone and rosiglitazone within a few minutes, have a more potent effect on Side effects occur in a small number of patients and enhancing first phase insulin secretion, are rapidly metab- have resulted in <1% withdrawal from clinical studies. olized in the liver, and are excreted mainly in bile. The Edema was reported in about 5%-15% of patients treated meglitinide analogues are short-acting. They appear to with pioglitazone in monotherapy and with different lower postprandial glucose levels more than the sulfonyl- combinations.39 Edema tended to be more severe in ureas and are associated with less hypoglycemia. Glucose combination with insulin and sulfonylureas as compared control, as measured by HbA1c, is equivalent to the to monotherapy. About 1%-6% of patients on rosiglita- sulfonylureas and metformin. These drugs are therefore zone experience edema.24,64 The differences in edema more suitable for patients with type 2 diabetes who have incidence could be related to design of the studies men- a variable lifestyle and elevated postprandial glucose tioned. In patients with history of CHF or NYHA class levels.12-16 Nateglinide is a phenylalanine derivative. In 3 and 4, the risk of heart failure is such that these drugs a study in a group of non-diabetic volunteers that should not be used. Decreased hemoglobin of 3 to compared nateglinide 120 mg to repaglinide 2 mg taken 10 gm/L was noted in some studies.24,39 An average 0.7- 10 min before food, nateglinide resulted in a more rapid 3.5 kg weight gain has been noted, related to both and short-lived stimulation of insulin secretion, resulting increased fat mass and fluid retention. A higher degree of in lower meal-related glucose excursions.17 Repaglinide is weight gain was noted when these drugs were combined available in Canada, while nateglinide, which is available with insulin.24,33 In long-term use, no significant hepatic in the United States and other countries, is not yet avail- toxicity has been observed. able in Canada. The recommended dose of repaglinide is 0.5 to 4 mg, up to 4 times a day; nateglinide is recom- Recommendations for pioglitazone and rosiglitazone use mended in a dosage of 120 mg tid, taken shortly before Both drugs are recommended in patients with type 2 meals. diabetes who are not adequately controlled or unable to
  3. 3. Table 1: Characteristics of the thiazolidinediones • Patients with a history of congestive heart failure, (pioglitazone, rosiglitazone) or in the NYHA class 3 and 4 should not be given thiazolidinediones. • There is evidence of preservation of islet cell insulin • Pregnancy: fertility may be restored in patients with content and improved beta cell function.26,28 polycystic ovary syndrome (PCO) as insulin resist- • Fat distribution studies suggest a decrease in visceral fat in the context of overall increased fat mass related to ance decreases. Precautions to prevent pregnancy increased peripheral fat. There was a significant reduc- should be discussed with the patient and docu- tion in waist/hip ratio in a 26-week study with rosiglita- mented until further experience is gained with zone.24,29,30 these drugs. • A slight decrease (2.3 mm Hg) in diastolic blood pres- sure was noted with rosiglitazone compared to baseline, Metformin and in systolic blood pressure with pioglitazone com- Metformin acts on the liver by reducing hepatic pared to acarbose (10 mm Hg decrease with pioglita- zone, compared to 1.5 mm Hg decrease with acar- glucose production. It suppresses gluconeogenesis bose).31,32 mainly by potentiating the effects of insulin, reducing • There is reduction in free fatty acid levels24 and a favor- hepatic extraction of certain substrates (eg, lactate), and able effect on lipid parameters with both pioglitazone opposing the effects of glucagon.41 Insulin-stimulated and rosiglitazone, reducing the LDL/HDL ratio. In studies glucose uptake into skeletal muscles is enhanced mainly with pioglitazone, there was a tendency towards more as a result of increased movement of glucose trans- reduction in triglyceride levels as compared to rosiglita- porters into the cell membrane.42 Metformin suppresses zone.24,33 However, there are no head to head com- parisons between these two drugs, making a definitive fatty acid oxidation and reduces hypertriglyceridemia. conclusion hard to ascertain. A meta-analysis of 9 randomized controlled trials • There is no evidence of clinically significant drug interac- compared metformin with sulfonylurea. Glucose was tions with other oral hypoglycemic agents, oral contra- reduced by 2 mmol/L and HbA1c by 0.9% compared to ceptives, nifedipine, digoxin, ranitidine, or war farin.33,34 placebo, with no significant weight change. These • Studies with rosiglitazone show that its pharmaco- results were similar to the sulfonylureas, except in terms kinetics are not altered in renally impaired patients or of body weight (an increase of 1.7 kg with sulfony- those on hemodialysis; as well, the pharmacokinetics lureas, compared to a 1.2 kg weight loss in metformin- of pioglitazone are not altered in moderate to severe renally impaired patients. Thus, there is no need to treated subjects).43 change the drug dosage in patients with impaired renal function.33-37 Alpha-glucosidase inhibitors • Preliminary studies with rosiglitazone show a tendency The alpha-glucosidase inhibitors inhibit the effects of towards decreased albumin excretion rate and intestinal enzymes responsible for carbohydrate absorp- albumin/creatinine ratio.24,38 This, however, has not yet tion. Alpha-glucosidases are enzymes located on the been verified in long-term controlled studies. brush border of the small intestine where they break down oligosaccharides and disaccharides into mono- tolerate their current oral hypoglycemic therapy. In saccharides, which are then absorbed in the proximal patients in whom other oral hypoglycemic therapies are jejunum. They do not directly affect beta cells and do contraindicated, the thiazolidinediones provide an effec- not cause hypoglycemia. They attenuate postprandial tive and safe alternative. I feel that the present data40 glycemia. There is minimal absorption of alpha-glucosi- justify the addition of a thiazolidinedione in patients who dase inhibitor from the gut, about 2%-3%; the rest remains are not meeting treatment targets while on maximum enteric.44 Both acarbose and miglitol reduce glucose less doses of combination sulfonylurea and metformin. It is effectively than glyburide (0.75% compared to 1%) and also my opinion that in certain patients who require large cause more gastrointestinal side-effects (flatulence seen amounts of insulin – especially if they are not attaining twice as much in the treatment group versus the control glycemic targets – the addition of a thiazolidinedione groups). They do not cause weight gain or hypo- could improve glucose parameters and reduce insulin glycemia.45 Acarbose is available in Canada, while miglitol dosage. This combination, however, should be used with is not. extreme caution because of the possibility of accelerated Both acarbose and miglitol are given at 50-100 mg edema, weight gain, and congestive heart failure. The tid, taken with the first bite of the meal. Starting with a recommended doses for pioglitazone are 15, 30, or 45 mg low dose (25 mg once daily), and gradually increasing once daily; for rosiglitazone, it is 4 mg once or twice per the dose, seems to reduce the gastrointestinal side effects. day or 8 mg once daily. Combination studies Contraindications Primary combination therapy • Abnormal liver function tests: AST > 2.5 times In a study by Herman et al, 56 newly diagnosed normal is a contraindication to starting patients on patients with type 2 diabetes were randomized to either this group of drugs to metformin or glyburide monotherapy, or a combination.
  4. 4. Follow-up for 6 months showed a decrease in fasting nateglinide and metformin groups, respectively. plasma glucose (FPG) by 3.2 mmol/L and in HbA1c Fasting plasma glucose was reduced by 2.4 versus by 1.5% in all groups. Weight increased by 3.1 kg in 1.6 and 2.4 mmol/L, respectively. The area under the the glyburide group, but stayed constant in the others.46 curve of glucose excursion was significantly lower A second study by Haupt et al,47 combining with both nateglinide and combination therapy com- metformin with a maximum dose of sulfonylurea, pared to placebo and metformin.50 in patients who failed monotherapy, resulted in a decrease in fasting plasma glucose by 2.8 mmo/L, Repaglinide + metformin postprandial glucose by 4.1 mmol/L, and HbA1c by 83 patients with type 2 diabetes who failed to 1.9%.47 achieve treatment targets while on treatment with In a third study,48 806 patients with newly diag- metformin (HbA1c >7.1%) were randomized to nosed type 2 diabetes who did not attain optimal metformin (n=27), repaglinide (n=29), or a combi- control with life-style changes were randomized to nation of both (n=27). The same metformin dose placebo, glyburide, metformin, and two fixed combi- was continued in patients receiving mono or com- nations of metformin/glyburide (M/G): 250/1.25 mg bination therapy; however, repaglinide was adjusted and 500/2.5 mg. Final doses for each active treatment over a 4-8 week titration period. Patients were group were: 5.3 mg glyburide; 1317 mg metformin, followed for a period of 3 months after reaching and 557/2.8 mg and 818/4.1 mg M/G, respectively. the final repaglinide dose. Fasting plasma glucose Decrease in HbA1c was significantly greater with the decreased by 2.2 mmol/L (P<0.0003) and HbA1c fixed combinations (1.48% and 1.53%, respectively), by 1.4% in the combination therapy group compared with placebo (0.21%), (P<0.001 for both); (P< 0.0016); 60% of the patients receiving combi- glyburide: 1.24%, (P<0.02 for M/G 250/1.25, and nation therapy reached HbA1c <7% compared to P<0.005 for M/G 500/2.5) and metformin: 1.03% only 20% in either monotherapy groups.51 (P<0.001 for both) at week 20. Sixty-five to 70% of patients on the fixed combinations reached HbA1c Other combination studies with repaglinide < 7%, significantly more than other treatment arms. Combination studies done with metformin, troglitazone, rosiglitazone, pioglitazone and insulin Combination therapy with oral agents showed a reduction in HbA1c by 1.3% to 1.7%.55-59 after failure with monotherapy Missed-lunch studies have shown less hypoglycemia Glyburide + metformin when compared to glyburide In a study by DeFronzo et al, 632 patients were treated with diet, or diet + a sulfonylurea. Open label Rosiglitazone and pioglitazone glyburide was stopped. Patients were randomized to: combination studies glyburide (n=209), metformin (n=210), or both medi- Studies combining rosiglitazone or pioglitazone cations (n=213). Fasting plasma glucose decreased by with sulphonylureas, metformin, and insulin showed 0.9 mmol/L in the glyburide group, 0.4 mmol/L in additional glucose lowering. Fasting plasma glucose the metformin group, and by 3.4 mmol/L in the and HbA1c showed significant decline. HbA1c group receiving the combination of both drugs declined by 1.6% to 1.7% compared to placebo.55-59 (P<0.001). HbA1c decreased by 0.2% in the gly- A recent study of triple therapy using troglitazone in buride group, 0.4% in the metformin group, and patients who fail to attain optimal glycemic control 1.7% in the combination therapy group (P<0.001). with maximum doses of metformin and glyburide, Body weight remained the same with glyburide, showed an average decrease in HbA1c of 1.4% com- decreased by 3.8 kg with metformin, and by 0.4 kg pared to placebo.40 At the present time, the glita- with the combination.49 zones are not currently indicated for use in combina- tion with insulin in Canada. Nateglinide + metformin 701 patients with type 2 diabetes were random- Alpha-glucosidase inhibitors ized to nateglinide 120 mg tid alone, metformin Combination therapy of acarbose 60,61 and migli- 62 500 mg tid alone, or a combination of nateglinide tol with sulfonylureas, metformin, and insulin 120 mg and metformin 500 mg tid after a washout results in a reduction in HbA1c of 0.5% to 1.4%. period. They were followed for 24 weeks. The results showed that HbA1c and FPG decreased more with Conclusion combination therapy as compared to monotherapy Glycemic control in patients with type 2 dia- (P<0.0001). HbA1c was reduced by 1.4% in the combi- betes should aim at normalization of glucose para- nation group compared to 0.5% and 0.8% in the meters: fasting, postprandial glucose and HbA1c. Endocrinology R OUNDS
  5. 5. 9. Duckworth WC, McCarren M, Abraira C, Veterans Affairs Diabetes Table 2: Rationale for targeting postprandial Trial (VADT), Glucose control and cardiovascular complications: the glucose levels VA Diabetes Trial. Diabetes Care 2001;24(5):942-945. 10. Tessier D, Dawson K, Tetrault JP, et al. Glibenclamide vs gliclazide in type 2 diabetes of the elderly. Diabet Med 1994;11(10):974-80. • Postprandial glucose levels correlate better with 11. Holstein P, et al. Glimepiride less hypoglycemia than glyburide. HbA1c values Diabetologia 2000;43:A40. • There is a correlation between postprandial glucose 12. Malaisse WJ. Stimulation of insulin release by non-sulfonylurea hypoglycemic agents: the meglitinide family. Horm Metab Res 1995; and cardiovascular disease (The DECODE study 63). 27:263-266. • The availability of interventions targeting post- 13. Wolffenbuttel BHR, Landgraf R, on behalf of the Dutch and German Repaglinide Study Group. A 1-year multi-center random- prandial glucose control: dietary interventions (high ized double-blind comparison of repaglinide and glyburide for the soluble fiber foods, foods with low glycemic index), treatment of type 2 diabetes. Diabetes Care 1999;22:463-467. insulin secretagogues of the meglitinide group, and 14. Nateglinide: A structurally novel insulin secretion agent. Drugs of rapid-acting insulin analogues Today 2001;37(suppl F)1-16. 15. Damsbo P, Clauson P, Marbury TC, et al. A double-blind randomized comparison of meal-related glycemic control by repaglinide and gly- buride in well controlled type 2 diabetic patients. Diabetes Care 1999;22:789-794. Early introduction of combination therapy with oral 16. Kristensen JS, Frandsen KB, et al. The frequency of severe hypo- glycemia is reduced with repaglinide treatment compared with agents is recommended, rather than the stepwise sulphonylurea treatment Eur J Endocrinol 1999;140(Suppl 1) approach presently advocated in the Clinical Prac- 19:Abstract 57. 17. Kalbag, JB, Walter,YH, Nedelman, JR, et al. Mealtime glucose regu- tice Guidelines. Target levels of control should be lation with nateglinide in healthy volunteers: comparison with the same as those found in people without diabetes. repaglinide and placebo. Diabetes Care 2001;24(1):73-77. 18. Lehmann JM, Moore LB, Smith-Oliver TA, et al. An antidiabetic thi- Failure of combination oral agents to attain such azolidinedione is a high affinity ligand for peroxisome proliferator- targets is an indication for additional therapy or activated receptor. J Biol Chem 1995;270:12953-12956 19. Saltiel AR, Olefsky JM. Thiazolidinediones in the treatment of substitution of insulin. Postprandial glucose levels insulin resistance and type II diabetes. Diabetes 1996;45:1661-1669. correlate with HbA1c and cardiovascular disease 20. Willson TM, Brown PJ, Sternbach DD, et al. The PPARs: from orphan receptors to drug discovery. J Med Chem 2000; 43:527-550. better than fasting glucose levels (Table 2). Targeting 21. Aronoff S, Rosenblatt S, Braithwaite S, et al. Pioglitazone hydrochlo- postprandial glucose levels is made possible by ride monotherapy improves glycemic control in the treatment of patients with type 2 diabetes. Diabetes Care 2000;23:1605-1611. interventions that improve first phase insulin secre- 22. Raskin P, Rappaport EB, Cole ST, et al. Rosiglitazone short-term tion, delay carbohydrate absorption, or provide monotherapy lowers fasting and postprandial glucose in patients with type II diabetes. Diabetologia 2000;43:278-284. rapid acting insulins. 23. Nolan JJ, Jones NP, Patwardhan R, et al. Rosiglitazone taken once daily provides effective glycemic control in patients with Type 2 dia- betes mellitus. Diabet Med 2000;17:287-294. Amir K. Hanna, MB, BCh, FRCPC, FACP, is an 24. Lebovitz HE, Dole J, Patwardhan R, et al. Rosiglitazone monothera- Associate Professor, Department of Medicine, py is effective in patients with type 2 diabetes. J Clin Endocrinol Metab 2001;86:280-288. University of Toronto, and Director, Diabetes Clinic, 25. Khan MA, St Peter JV, Neafus KL, et al. A prospective, randomized St. Michael’s Hospital, Toronto, Ontario comparison of the metabolic effects of pioglitazone in patients with type 2 diabetes who were previously treated with troglitazone. Diabetes 2001;50(Suppl.2):A119. References 26. Matthews DR, Bakst A, Weston WM, et al. Rosiglitazone decreases 1. The Diabetes Control and Complications Trial Research Group. The insulin resistance and improves beta-cell function in patients with effect of intensive therapy of diabetes on the development and pro- type 2 diabetes. Diabetologia 1999;42(Suppl 1): Abstract 858. gression of long-term complications in insulin-dependent diabetes 27. Rosenstock J, for the pioglitazone HCI study group. Improved mellitus. N Engl J Med 1993;329: 977-986. insulin sensitivity and beta cell response with pioglitazone therapy 2. Ohkubo Y, Kishikawa, H, Araki E, et al. Intensive insulin therapy pre- suggested by HOMA analysis. Diabetologia 2000; 43(Suppl 1):A192. vents the progression of diabetic microvascular complications in 28. Jones NP, et al. Rosiglitazone reduces plasma insulin and its precur- Japanese patients with non-insulin dependent diabetes mellitus: a sors while decreasing glycemia in type 2 diabetes. Diabetes 1999;48 randomized prospective 6-year study. Diabetes Res Clin Pract 1995; (Suppl 1):Abstract 859. 28:103-117. 29. Kelly IE, Han TS, Walsh K, et al. Effects of a thiazolidinedione com- 3. UKPDS Group. Intensive blood glucose control with sulphonylureas pound on body fat and fat distribution of patients with type 2 dia- or insulin compared with conventional treatment and risk of betes. Diabetes Care 1999;22:288-293. complications in patients with type 2 diabetes (UKPDS 33). Lancet 30. Miyazaki,Y, Mahankali A, Matsuda M, et al. Effect of pioglitazone on 1998;352:837-853. abdominal fat distribution and insulin sensitivity in patients with 4. Stratton IM, Adler AL, Neil HA, et al. Association of glycaemia with type 2 diabetes mellitus (T2DM). Diabetes 2000;49(Suppl.1):A299. macrovascular and microvascular complications of Type 2 Diabetes 31. St John Sutton M, Dole J, Rappaport EB. Rosiglitazone does not (UKPDS 35): prospective observational study. BMJ 2000;321:405- adversely affect cardiac structure or function in patients with type 2 412. diabetes. Diabetes 1999;42(Suppl 1):A102. 5. Retinopathy and nephropathy in patients with type 1 diabetes four 32. Scherbaum W, Goke B, for the German Pioglitazone Study Group, years after a trial of intensive therapy. The Diabetes Control and Dusseldorf and Munich, Germany. Pioglitazone reduces blood pres- Complications Trial/ Epidemiology of Diabetes Interventions and sure in patients with type 2 diabetes mellitus. Diabetes 2001;50 Complications Research Group. N Engl J Med 2000;342(6):381- (Suppl 2):A462. 389. 33. Avandia (rosiglitazone maleate) Product Monograph, CPS. 6. Shichiri M, Kishikawa H, Ohkubo Y, Wake N. Long-term results of 34. Crijns-Kortboyer J, Eckland D. Pioglitazone has low potential for the Kumamoto study on optimal diabetes control in diabetic drug interaction. Diabetologia 1999;42(Suppl 1):A228. patients. Diabetes Care 2000;23(suppl 2):B21-9. 35. Chapelsky MC, Thompson K, Miller A. Effect of renal impairment 7. Meltzer S, Leiter L, Daneman D, et al. 1998 Clinical Practice on the pharmacokinetics of rosiglitazone (RSG). Clin Pharmacol Guidelines for the Management of Diabetes in Canada. CMAJ 1998; Ther 1999;65:185. 159 Suppl 8:S1-29. 36. Thompson K, Zussman B, Miller A. Pharmacokinetics of rosiglita- 8. Action to Control Cardiovascular Disease in Diabetes (ACCORD) zone are unaltered in hemodialysis patients. Clin Pharmacol Ther Study Protocol 2. 1999;65:186. Endocrinology R OUNDS
  6. 6. 37. Edwards G, Eckland D. Pharmacokinetics of pioglitazone in patients with Abstract of Interest renal impairment. Diabetologia 1999;42(Suppl 1)A228. Nateglinide is safe and efficacious in lowering postprandial blood glu- 38. Bakris G,Weston WM, Rappaport EB, et al. Rosiglitazone produces cose in Type 2 diabetic patients with various degree of renal function. long-term reductions in urinary albumin excretion in type 2 diabetes. Diabetologia 1999;42(Suppl 1):A865. TOMOFUSA ISHII, TETSUYA YAMAKITA, KEIKO YAMAGAMI, ET AL. OSAKA, JAPAN. 39. Aronoff SL. Adverse events with pioglitazone HCL. Diabetes 2000; Impaired renal function results in reduced excretion of most oral hypo- 49(Suppl 1):A340. glycemic agents (OHAs) and its metabolites, increasing the duration of 40. Yale JF, Valiquett TR, Ghazzi MN, et al. The effect of a thiazolidinedione drug action and increasing the risk of hypoglycemia. Nateglinide (NAT) is drug, troglitazone, on glycemia in patients with type 2 diabetes mellitus poorly controlled with sulfonylurea and metformin. A multicenter, ran- a novel OHA that acts by stimulating the secretion of insulin but is unique domized, double-blind, placebo controlled trial. Ann Intern Med 2001; among OHAs in its short biological half-life and largely nonrenal route of 134:737-741. excretion, so it may be safe and efficacious in lowering postprandial blood 41. Wiernsperger, NF, Bailey, CJ. The antihyperglycaemic effect of metformin: glucose in Type 2 diabetes even with renal impairment. We examined therapeutic and cellular mechanisms. Drugs 1999; 58(Suppl 1): 31-39. this issue in 8 inpatients with Type 2 diabetes with various degrees of 42. Klip, A, Leiter, LA. Cellular mechanism of action of metformin. Diabetes renal function (male/female: 4/4, age: 64±6 years, BMI 22.3±1.9 kg/m2 Care 1990;13 (6):696-704. Review. HbA1c 7.8±1.3%, fasting plasma glucose 169±54 mg/dl, creatinine clear- 43. Johansen K. Efficacy of metformin in the treatment of NIDDM. Meta- analysis. Diabetes Care 1999;22(1):33-37. ance [CLCR] 41.8±16.2 ml/min, 71.5 to 21.6 ml/min, mean±SD), who 44. Caspry, WF. Sucrose-malabsorption in man after ingestion of alpha-glu- were not administrated any OHAs. Participants were examined on 2 con- cosidehydrolase inhibitor. Lancet 1978;1:1231-1233. secutive days without (Day 1) or with (Day 2) an administration of NAT 45. Segal,P., Feig PU, Schernthaner, G, et al. The efficacy and safety of miglitol (90 mg) before a standardized breakfast, and 6 days after the NAT therapy compared with glibenclamide in patients with NIDDM inade- therapy (270 mg/day, 3 times before meals) (Day 7). Postprandial glucose, quately controlled by diet alone. Diabetes Care 1997; 20(5):687-691. concentrations of insulin, C-peptide, plasma NAT and its major metabo- 46. Hermann LS, Bitzen PO, Kjellstrom T, et al. Comparative efficacy of met- lite (M1) were measured every hour on Day 1 and Day 2. Postprandial formin and glibenclamide in patients with non-insulin-dependent diabetes glucose was lower and the concentrations of insulin and C-peptide were mellitus. Diabete Metab 1991;17:201-208. 47. Haupt E, Knick B, Koschinsky T, et al. Oral antidiabetic therapy with higher on Day 2 compared with those on Day 1 (p<0.05, respectively). sulphonylureas and metformin. Diabetes Metab 1991;17:224-231. The ratio of Day 2 to Day 1 for insulin concentrations had no relation to 48. Garber A, Davidson J, Mooradian A, et al. Effect of metformin/glyburide CLCR (r=0.09). The concentrations of NAT (4.4±0.9 microg/ml) and M1 tablets on HbA1C in first-line treatment of type 2 diabetes. Diabetes 2000; (1.1±0.6 microg/ml) peaked 1 hour after an administration of NAT in all 49(suppl 1): Abstract 432- P patients, and area under the curve for the concentrations of NAT and M1 49. DeFronzo R, Goodman AM. Efficacy of metformin in patients with non- had no relation to CLCR (r=0.08 and r=1.82, respectively). There insulin-dependent diabetes mellitus. The Multicenter Metformin Study observed no significant increase in the concentration of fasting insulin on Group. N Engl J Med 1995;333(9):541-549. 50. Horton ES, Clinkingbeard C, Gatlin M, et al. Nateglinide alone and in com- Day 7 compared with that on Day 1 and Day 2 (4.4±1.2, 4.2±1.4 and bination with metformin improves glycemic control by reducing mealtime 4.8±1.6 microU/ml, respectively), and no accumulation of plasma NAT glucose levels in type 2 diabetes. Diabetes Care 2000;23(11):1660-1665. or M1 early in the morning on Day 7. It is concluded that NAT is safe and 51. Moses R, Slobodniuk R, Boyages S, et al. Effect of repaglinide addition to efficacious in lowering postprandial blood glucose in Type 2 diabetes with metformin monotherapy on glycemic control in patients with type 2 dia- mild-to-moderate renal impairment. betes. Diabetes Care 1999;22:119-122. 52. Jovanovic L, Jain R, Greco S, et al. Repaglinide/pioglitazone combination therapy in type 2 diabetes [Abstract]. Diabetes 2001; 50(Suppl.2):Abstract 1830-PO. Upcoming Meetings 53. Landin-Olsson M, Brogard JM, et al. The efficacy of repaglinide adminis- tered in combination with bedtime NPH-insulin in patients with type 2 1-3 February, 2002 diabetes [Abstract]. Diabetes 1999;46(Suppl 1):A117. Abstract 0503. American Diabetes Association 54. Eriksson JG, Brogard JM, et al. The safety of repaglinide administered in 49th Annual Advanced Postgraduate Course combination with bedtime NPH-insulin in patients with type 2 diabetes [Abstract]. Diabetes 1999;48(Suppl 1):A360. Abstract 1575. San Francisco, California 55. Schneider R, Egan J, Houser V. Combination therapy with pioglitazone and CONTACT: ADA Meeting Services Department sulfonylurea in patients with type 2 diabetes. Diabetes 1999;48(Suppl 1): Tel: 703 549-1500 Ext. 2022 A106. 56. Einhorn D, Rendell M, Rosenzweig J, et al. Pioglitazone hydrochloride in E-mail: meetings@diabetes.org combination with metformin in the treatment of type 2 diabetes mellitus: a randomized, placebo-controlled study. Clin Ther 2000; 22:1395-1409. 14-18 June, 2002 57. Rubin C, Egan J, Schneider R. Combination therapy with pioglitazone and insulin in patients with type 2 diabetes. Diabetes 1999; 48(Supp1):A110. American Diabetes Association 62nd Annual Meeting and 58. Fonseca V, Rosenstock J, Patwardhan R, et al. Effect of metformin and Scientific Sessions rosiglitazone combination therapy in patients with type 2 diabetes melli- San Francisco, California tus. JAMA 2000;283:1695-1702. 59. Gomis R, Jones NP, et al. Low-dose rosiglitazone enhances glycaemic con- CONTACT: ADA Meeting Services Department trol when combined with sulphonylureas in type 2 diabetes. Poster presen- Tel: 703 549-1500 Ext. 2134 tation at the 59th American Diabetes Association Annual Meeting; June E-mail: meetings@diabetes.org 19-22, 1999; San Diego, California: Poster 266 60. Holman RR, Cull CA, Turner RC. A randomized double-blind trial of acar- bose in type 2 diabetes shows improved glycemic control over 2-5 October 2002 3 years (U.K. Prospective Diabetes Study 44) Diabetes Care 1999;22(6): Canadian Diabetes Association and the Canadian Society 960-964. of Endocrinology Metabolism 61. Chiasson JL, Josse RG, Hunt JA, et al. The efficacy of acarbose in the treat- ment of patients with non-insulin-dependent diabetes mellitus. A multi- Professional Conference and Annual Meetings center controlled clinical trial. Ann Intern Med 1994; 121(12):928-935. Vancouver, British Columbia 62. Chiasson JL, Naditch L.The synergistic effect of miglitol plus metformin CONTACT: Helena Miekus combination therapy in the treatment of type 2 diabetes. Diabetes Care 2001; 24(6):989-94. Tel: 416 363-0177 Ext. 571 63. Balkau B. The DECODE study. Diabetes epidemiology: collaborative analy- Fax: 416 363-7465 sis of diagnostic criteria in Europe. Diabetes Metab 2000; 26(4):282-6. E-mail: helena.miekus@diabetes.ca 64. Phillipis LS, Grunberger G, Miller E, et al. Once- and twice-daily dosing with rosiglitazone improves glycemic control in patients with Type 2 dia- betes. Diabetes Care 2001;24:308-315. Provided as a service to medicine through an educational grant from Aventis Pharma © 2001 The Division of Endocrinology and Metabolism, St. Michael’s Hospital, which is solely responsible for the contents. The opinions expressed in this publication do not necessarily reflect those of the publisher or sponsor, but rather are those of the authoring institutions based on the available scientific literature. Publisher: SNELL Medical Communication Inc. in cooperation with The Division of Endocrinology and Metabolism. All rights reserved. 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